Project Summary/Abstract Objective: To identify common and rare genetic variants which increase the risk of schizophrenia. Specific Aims: 1. To sequence a linked region on chromosome 5q. 2. To rank the most promising variants discovered in Aim 1 using a combination of statistical and bioinformatics criteria. 3. To determine whether genetic risk variants discovered in (1) are associated with schizophrenia our sample, the Portuguese Island Collection (PIC). This will be done by genotyping the 1536 most promising variants in Aim 2 in 400 cases and 400 controls. Background: Schizophrenia is a major health concern in the Veterans Health Administration. Linkage studies of schizophrenia performed in multiple independent samples have repeatedly implicated chromosome 5q. We observed linkage in the PIC using two independent sets of genetic markers (microsatellites as well as Single Nucleotide Polymorphsims [SNPs]). Very recently published genome-wide association studies (GWAS) of large samples (which have included the PIC), strongly implicate rare variants in the pathogenesis of schizophrenia. Resequencing will be a necessary strategy in mapping disease variants, as standard methods of association mapping may not be able to detect them. In the last funding period, our GWAS of the PIC demonstrated a cluster of associated SNPs in and around the gene encoding the ionotropic glutamate receptor, AMPA 1 isoform (GRIA1), which is on 5q. This finding is strongly supported by the Glutamate Hypothesis of schizophrenia. Proposed Methods: We plan to sequence 30 MB of the chromosome 5q linkage region in 24 sibling pairs concordant for schizophrenia and 24 controls. In the first, or discover phase, we will exploit the family-based structure of the PIC, which is derived from a population isolate. Variants will be prioritized if they are shared by affected siblings, but do not occur in controls. We plan to use NimbleGen Sequence Capture arrays to partition the 5q region in the most efficient manner possible. This will be followed by sequencing using the "next generation" Illumina Genome Analyzer II. In the second, or association phase, we will test the 1536 SNPs having highest priority, in 400 cases and 400 controls in the PIC using the Illumina GoldenGate assay. PUBLIC HEALTH RELEVANCE: Project Narrative Schizophrenia is a devastating neuropsychiatric condition with an annual cost of $36.5 billion in the United States, making it a major public health concern. There are an estimated 90,000 patients with schizophrenia or other psychotic illnesses in the VA system nationwide. Although significant progress has been made in uncovering the genetic basis of schizophrenia, there are currently no specific genetic changes (mutations) known to cause illness across various ethnic groups. Most previous studies have only been able to identify relatively common mutations. Therefore, it will be important to use other ways of searching for mutations, as they may be rare. Determining the genetic sequence of regions of the genome is needed in order to identify rarer mutations, which are more likely to directly cause disease. The identification of such mutations may provide vital clues as to the causes of the illness as well as new treatments. In this project, we seek to determine the genetic sequence of individuals with schizophrenia and search for both common and rare mutations.